Virologists at the National Cancer Institute are looking for a few goodfirms to enlist in a task force deploying new weapons against HIV andother lentiviruses.The field manual for this lateral thinking in designing an AIDS vaccinewith a difference is a pending U.S. patent titled: "ImmunologicalFocusing of Protective Effective Responses Using Site-DirectedMutagenesis or Chemical Modification to Alter a Specific Protein orPeptide Immunogen for Use in Plant, Animal and Human Vaccines andImmunotherapies."The innovation's lead inventor is molecular biologist Robert Garrity.He works with Peter L. Nara, who heads the VIrus Biology Section ofthe Tumor Cell Biology Laboratory at the National Cancer Institute'sresearch and development branch in Frederick, Md.An announcement in the Federal Register last month invited interestedpharmaceutical or biotechnology companies to apply for an exclusiveor non-exclusive CRADA (Cooperative Research & DevelopmentAgreement) to team up with Nara's unit in commercializing this "novelapproach for HIV-1 vaccine development."The partner-recruiting notice added, "Any CRADA for the biomedicaluse of this technology will be considered."Deception Vs. DisinformationNara told BioWorld Today what's novel about his group'simmunological strategy to sneak up on HIV's so- far vaccine-proofdefenses. "Our working hypothesis for AIDS," he said, "is that theimmune response is misdirected, and attenuated by the invadingpathogen, to allow for a chronic active infection to take hold."Virtually all AIDS vaccines currently under development, but none yetsuccessful, Nara noted, aim their antibodies at antigenic glycoproteinson the viral envelope's outer surface _ gp120, gp160 and (internal)gp24. Portions of the gp120 envelope protein apparently smuggle HIV-1 particles into the host's immune regulatory network, and provokelymphocytes (cells that orchestrate the immune system) to commitapoptosis _ biological harakiri.HIV, like influenza virus, is famous, or infamous, for its variability _constantly changing its antigenic spots by rapid, spontaneous mutation.When the virus first infects the body of its victim by pumping in cell-free virion particles, the host's immune system kicks in and foments anadvance party of antibodies programmed against dominantdeterminants on the hypervariable domain (V3) and gp41transmembrane domain of gp160, the major envelope glycoprotein."Let's say," Nara said, "that the virus is smart enough to give falseimmunodominant epitopes, which are decoying or disregulating. Thismay be part of a viral adaptation to decoy and focus the initial cellularand humoral (antibody-generating B-cell) response to V3, whichresults in a diversion of the immune response away from moreprotective gp160 targets."Soon after its initial infective burst, the virus foresakes V3 for V1epitopes, but the body's antibody-generating repertoire in a senseremains fixated on the initial V3 region, which is long gone as a first-line antigenic target. Nara and his co-inventors call this left-in-the-lurch syndrome "repertoire freeze." An influenza researcher 40 yearsago called it "original antigenic sin.""This repertoire freeze," Nara speculates, "appears to be responsible forlimiting the recruitment of new, uncommitted B cells to otherfunctional epitopes."Sugar-Coating The TargetThe NCI researchers' counter- measure is to mask or cloak thosedominant epitopes, on which the V3 antibodies continue to focus, witha non- or weakly immunogenic coating of recombinant sugar _carbohydrate. This site- directed mutagenesis strategy, tested in guineapigs, thawed the frozen antibodies so they could hunt down andneutralize the new crop of variable epitopes. "We hope that these,"Nara said, "are Achilles' heels to the virus." He added, "The approachof unmasking or redirecting the immune response away from theseepitopes may be useful in developing future vaccines."Now, his laboratory is "mapping the retroviral immunogenic hierarchyinvolved in decoying, attenuating or suppressing enhancing epitopesagainst the host immune response." It is also planning to do in vivosafety and efficicacy studies in the HIV- 1 chimp model.The company or companies accepted for CRADAs would finance andconduct human trials, as well as testing subunit HIV- 1 candidatevaccines in vitro and in vivo.The research and development partnership, Nara added, "would alsoenable extension of the technology to other novel biopharmaceuticalapplications, including lentiviruses in veterinary medicine," underseparate CRADAs. n[Editor's Note: For further information on these CRADA opportunities,contact Raphe Kantor, NCI (Frederick) Office of TechnologyDevelopment, (301) 846- 1501. ]

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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